Preserved T-Cell Function in Children and Young Adults With Immune-Tolerant Chronic Hepatitis B
Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England. Gastroenterology
(Impact Factor: 16.72).
06/2012; 143(3):637-45. DOI: 10.1053/j.gastro.2012.06.009
Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance.
We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells.
Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB.
HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.
Available from: Antonio Bertoletti
- "A direct demonstration that the “immunotolerance” phase is not associated with an absence of virus-specific T cell immunity came directly from our recent study of chronic hepatitis B (CHB)-infected adolescents. Despite having a clinical and virological profile labeled as “immunotolerant,” these adolescents displayed a perfectly normal Th1 T cell response and harbored HBV-specific T cells that were actually functionally better than the ones detected in adult CHB patients in the “immune clearance” phase (36). "
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ABSTRACT: Immune responses change during the life of an individual. While this concept has been well accepted for adaptive immunity, only recently it is becoming clear that the innate immune responses also acquire distinct features in different phases of life. We believe that this concept can offer a different interpretation of the pathological manifestations that can be observed in HBV-infected subjects during the patient's life. Here, we will review the age-related immunopathological features of HBV infection and discuss how the different virological and clinical manifestations might be linked to the developmental pathway of the immune system from newborns to adults. We will discuss how the age of patients can affect the degree of inflammatory responses, but not the levels of antiviral specific immunity. We then propose that the different clinical manifestations occurring during the natural history of HBV infection are related to the host ability to trigger an inflammatory immune response.
Available from: Takahito Yagi
- "In non-OLT HBV patients, analysis has revealed that HBsAg-positive newborns had higher regulatory T-cell frequencies and dysfunctional CD8 T cells, which represent immune tolerant status . However, another report analyzing the immunological characteristics of HBsAg-positive young carriers and aged patients with active hepatitis revealed comparable peripheral T-cell proinflammatory cytokine production capacity and HBV-specific IFN-γ responses . These findings indicate that tolerant carriers can react with HBV antigens and can show active immunity against HBV vaccination, if regulatory T-cell function diminishes. "
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ABSTRACT: Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV) reinfects transplanted livers at a rate of >90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C.
Available from: nature.com
- "At this point, it is important to note that in contrast to adult-onset HBV infection more than 90% of newborns exposed to HBV at birth become persistently infected. However, a study performed by Kennedy et al.53 has suggested that chronic HBV infection in children is not associated with a compromised or tolerogenic T-cell profile suggesting that other mechanisms may contribute to the elevated rate of persisting HBV infection in children. "
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ABSTRACT: Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are global health problems affecting 600 million people worldwide. Indeed, HBV and HCV are hepatotropic viruses that can cause acute and chronic liver disease progressing to liver cirrhosis and even hepatocellular carcinoma. Furthermore, co-infections of HBV and HCV with HIV are emerging worldwide. These co-infections are even more likely to develop persistent infection and are difficult to treat. There is growing evidence that virus-specific CD4+ and CD8+ T-cell responses play a central role in the outcome and pathogenesis of HBV and HCV infection. While virus-specific T-cell responses are able to successfully clear the virus in a subpopulation of patients, failure of these T-cell responses is associated with the development of viral persistence. In this review article, we will discuss similarities and differences in HBV- and HCV-specific T-cell responses that are central in determining viral clearance, persistence and liver disease.
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